Stabilized tablet formulation

ABSTRACT

PCT No. PCT/US94/09945 Sec. 371 Date May 11, 1995 Sec. 102(e) Date May 11, 1995 PCT Filed Sep. 2, 1994 PCT Pub. No. WO95/06461 PCT Pub. Date Mar. 9, 1995Invented are stabilized tablet formulations of substituted 3,5-diene steroidal compounds. Also invented are methods of preparing stabilized tablet formulations of substituted 3,5-diene steroidal compounds.

This application is a 371 of PCT/US94/09945 filed Sep. 2, 1994.

The present invention relates to novel stabilized tablet formulations ofsubstituted 3,5-diene steroidal compounds containing a 3 positionelectron-withdrawing group and methods of preparing stabilized tabletformulations of substituted 3,5-diene steroidal compounds containing a 3position electron-withdrawing group. Preferably, this invention relatesto novel stabilized tablet formulations of substituted 3,5-dienesteroidal compounds containing a 3 position acid group and methods ofpreparing stabilized tablet formulations of substituted 3,5-dienesteroidal compounds containing a 3 position acid group. Preferably, thisinvention relates to novel stabilized tablet formulations of substituted3,5-diene steroidal compounds containing a 3 position carboxylic acidgroup and methods of preparing stabilized tablet formulations ofsubstituted 3,5-diene steroidal compounds containing a 3 positioncarboxylic acid group. Advantageously, the substituted 3,5-dienesteroidal compound for use in the presently invented stabilized tabletformulations and presently invented methods isN-t-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid.

DETAILED DESCRIPTION OF THE INVENTION

Novel substituted 3,5-diene steroidal compounds containing a 3 positionelectron-withdrawing group have recently been shown to exhibitsignificant pharmaceutical activity. Specifically, said compounds havebeen found to inhibit steroid 5-α-reductase and are thereby useful inthe treatment of prostate diseases such as benign prostatic hypertrophy.Stabilized tablet formulations of substituted 3,5-diene steroidalcompounds containing a 3 position electron-withdrawing group areadvantageous in preparing dosage units for oral administration.

By the term "substituted 3,5-diene steroidal compound" as used herein ismeant a compound of the figure ##STR1## wherein W is anelectron-withdrawing group; and the C₁ and C₂ positions and the C₈ toC₁₉ positions are optionally substituted with pharmaceuticallyacceptable substituents, degrees of unsaturation or a combination ofpharmaceutically acceptable substituents and degrees of unsaturation.

The term "electron-withdrawing group" is well known to those of skill inthe art and is used herein as its standard meaning which is a functionalgroup that draws electrons to itself more than a hydrogen atom would ifit occupied the same position in the molecule, as described in J. March,Advanced Organic Chemistry, third edition, Pub: John Wiley & Sons, Inc.(1985). Preferred electron-withdrawing groups for use in the presentlyinvented stabilized tablet formulations and presently invented methodsare: --COOH, --P(O)(OH)₂, --PH(O)OH, --SO₃ H, --CHO, --CONHSO₂ R²⁰ whereR²⁰ is an alkyl group having from 1 to 6 carbon atoms, --CN, --CONH₂and, where appropriate, esters thereof.

By the term "acid group" as used herein is meant a substituent selectedfrom the group consisting of: --COOH, --P(O)(OH)₂, --PH(O)OH and --SO₃H.

The most preferred electron-withdrawing group for use in the presentlyinvented stabilized tablet formulations and presently invented methodsis --COOH.

By the term "fatty acid" as used herein is meant saturated andunsaturated fatty acids of the standard usage wherein the compoundcontains from about 10 to 22 carbon atoms, preferably decanoic acid,stearic acid, palmitic acid, oleic acid, lauric acid or myristic acid;most preferably, stearic acid.

Preferred substituted 3,5-diene steroidal compounds for use in thepresently invented stabilized tablet formulations and presently inventedmethods include compounds of the Formula I ##STR2## wherein R is ahydrocarbon radical selected from substituted or unsubstituted 1- or2-adamantyl, 1-, 2- or 7-norbornanyl.

Included within the scope of compounds of Formula I are those whereinthe 1- or 2-adamantyl or 1-, 2- or 7-norbornanyl moieties aresubstituted with one or more of: C₁ -C₄ linear or branched alkyl; nitro;oxo; C₇ -C₉ arylalkyl, including benzyl; (CH₂)_(n) COOR¹ where n is 0-2and R¹ is H or linear or branched C₁ -C₄ alkyl; CH₂ 0H; OH; OR² where R²is C₁ -C₄ linear or branched alkyl; halo; CONH₂ ; CH₂ NH₂ ; CH₂ NHCOR³where R³ is C₁ -C₄ linear or branched alkyl; phenyl and p-substitutedphenyl wherein the substituents are members selected from the groupconsisting of nitro; amino; sulfo and cyano.

Compounds of Formula I and methods of preparing compounds of Formula Iare described in EPO Publn. No. 0465141 (Published 8 Jan. 1992) toRasmusson, et al. (Merck Co. Inc.). Said compounds are disclosed thereinas being useful in inhibiting steroid 5-α-reductase.

Preferred substituted 3,5-diene steroidal compounds for use in thepresently invented stabilized tablet formulations and presently inventedmethods include compounds of the Formula II ##STR3## wherein R is C₁ -C₆linear or branched alkyl; C₃ -C₈ cycloalkyl, which can be substitutedwith C₁ -C₄ alkoxy or C₁ -C₄ linear or branched alkyl; C₆ -C₁₂ aryl,which can be substituted with one or more of: --OH, --OC₁ -C₄ alkyl, C₁-C₄ alkyl, --(CH₂)_(m) OH,--(CH₂)_(n) COOH, including protected --OH,where m is 1-4 and n is 1-3.

Additionally preferred substituted 3,5-diene steroidal compounds for useherein are the ketone reduction products of II, the secondary alcoholsof the formula ##STR4## wherein R is C₁ -C₆ linear or branched alkyl; C₃-C₈ cycloalkyl, which can be substituted with C₁ -C₄ alkoxy or C₁ -C₄linear or branched alkyl; C₆ -C₁₂ aryl, which can be substituted withone or more of: --OH, --OC₁ -C₄ alkyl, C₁ -C₄ alkyl, --(CH₂)_(m) OH,--(CH₂)_(n) COOH, including protected --OH, where m is 1-4 and n is 1-3.

Compounds of Formula II and the ketone reduction products of II andmethods of preparing compounds of Formula II and the ketone reductionproducts thereof are described in EPO Publn. No. 0465142 (published 8Jan. 1992) to Rasmusson, et al. (Merck & Co. Inc.). Said compounds andketone reduction products thereof are disclosed therein as being usefulin inhibiting steroid 5-α-reductase.

Particularly preferred substituted 3,5-diene steroidal compounds for usein the presently invented stabilized tablet formulations and presentlyinvented methods include compounds of the Formula III ##STR5## in which;R² is H or CH₃ and

R³ is

(1) α-hydrogen, α-hydroxyl, or α-acetoxy and/or ##STR6## where W is abond or C₁₋₁₂ alkyl, and R⁴ is (i) hydrogen,

(ii) hydroxyl,

(iii) C₁₋₈ alkyl,

(iv) hydroxy C₁₋₈ alkyl,

(v) C₁₋₈ alkoxy,

(vi) NR⁵ R⁶, where R⁵ and R⁶ are each independently selected fromhydrogen, C₁₋₈ alkyl, C₃₋₆ cycloalkyl, phenyl; or R⁵ and R⁶ takentogether with the nitrogen to which they are attached represent a 5-6membered saturated ring comprising up to one other heteroatom selectedfrom oxygen and nitrogen, or

(vii) OR⁷, where R⁷ is hydrogen, alkali metal, C₁₋₁₈ alkyl,benzyl, or

(b) β-Alk-OR⁸, where Alk is C₁₋₁₂ alkyl, and R⁸ is

(i) phenylC₁₋₆ alkylcarbonyl,

(ii) C₅₋₁₀ cycloalkylcarbonyl,

(iii) benzoyl,

(iv) C₁₋₈ alkoxycarbonyl,

(v) aminocarbonyl, or C₁₋₈ alkyl substituted aminocarbonyl,

(vi) hydrogen, or

(vii) C₁₋₈ alkyl,

(2) ═CH--W--CO-R⁴ or ═CH--W--OR⁸, where W is a bond or C₁₋₁₂ alkyl andR⁴ and R⁸ have the same meaning as above and R⁸ also is hydrogen orC₁₋₂₀ alkylcarbonyl; ##STR7## where the dashed bond replaces the17-α-hydrogen, (4) α-hydrogen and β-NHCOR⁹ where R⁹ is C₁₋₁₂ alkyl orβ-NR⁵ R⁶ where R⁵ and R⁶ have the same meaning as above,

(5) α-hydrogen and β-cyano,

(6) α-hydrogen and β-tetrazolyl, or

(7) keto.

Compounds of Formula III and methods of preparing compounds of FormulaIII are described in U.S. Pat. No. 5,017,568. Said compounds aredisclosed therein as being useful in inhibiting steroid 5-α-reductase.

Particularly preferred substituted 3,5-diene steroidal compounds for usein the presently invented stabilized tablet formulations and presentlyinvented methods include compounds of the formula (IV) ##STR8## whereinY is oxygen or sulphur,

R₁ is methyl, ethyl, isopropyl, tert-butyl, cyclohexyl; and the group##STR9##

Compounds of formula IV and methods of preparing compounds of formula IVare described in U.S. Pat. No. 5,212,166. Said compounds are disclosedtherein as being useful in inhibiting steroid 5α-reductase.

Particularly preferred substituted 3,5-diene steroidal compounds for usein the presently invented stabilized tablet formulations and presentlyinvented methods include compounds of the formula (V) ##STR10## wherein:R¹ represents: a hydrogen atom; an alkyl group having from 1 to 6 carbonatoms; or a substituted alkyl group having from 1 to 6 carbon atoms andhaving at least one substituent selected from aryl groups as definedbelow and aromatic heterocyclic groups as defined below;

R² represents:

a substituted alkyl group having from 1 to 6 carbon atoms and having atleast one substituent selected from aryl groups as defined below andaromatic heterocyclic groups as defined below, and said alkyl groupfurther optionally having a single hydroxy or carboxy substituent; or

a diaryamino group in which the two aryl parts are the same or differentand each is as defined below;

R³ represents a carboxy group or a group of formula --CONHSO₂ R⁴ whereinR⁴ represents an alkyl group having from 1 to 6 carbon atoms; said arylgroups are carbocyclic aromatic groups having from 6 to 14 ring carbonatoms and which are unsubstituted or are substituted by at least onesubstituent selected from substituents A, defined below;

said aromatic heterocyclic groups have 5 or 6 ring atoms of which from 1to 3 are hetero-atoms selected from nitrogen, oxygen and sulphurhetero-atoms and the remainder are carbon atoms, said group beingunsubstituted or being substituted by at least one substituent selectedfrom substituents B, defined below;

said substituents A are selected from: alkyl groups having from 1 to 6carbon atoms; alkoxy groups having from 1 to 6 carbon atoms;alkoxycarbonyl groups having from 2 to 7 carbon atoms; hydroxy groups;halogen atoms; amino groups; alkylamino groups having from 1 to 6 carbonatoms; dialkylamino groups in which each alkyl part has from 1 to 6carbon atoms; aliphatic acylamino groups having from 1 to 6 carbonatoms; aromatic acylamino groups in which the aromatic part is acarbocyclic aryl group which has from 6 to 10 ring carbon atoms andwhich is unsubstituted or is substituted by at least one substituentselected from substituents C, defined below; cyano groups; nitro groups;and carboxy groups;

said substituents B are selected from: alkyl groups having from 1 to 6carbon atoms; alkoxy groups having from 1 to 6 carbon atoms; hydroxygroups; halogen atoms; carbocyclic aryl groups which have from 6 to 10ring carbon atoms and which are unsubstituted or are substituted by atleast one substituent selected from substituents C, defined below: aminogroups; alkylamino groups having from 1 to 6 carbon atoms; dialkylaminogroups in which each alkyl part has from 1 to 6 carbon atoms;

aliphatic acylamino groups having from 1 to 6 carbon atoms; aromaticacylamino groups in which the aromatic part is a carbocyclic aryl groupwhich has from 6 to 10 ring carbon atoms and which is unsubstituted oris substituted by at least one substituent selected from substituents C,defined below; nitro groups; and carboxy groups;

said substituents C are selected from: alkyl groups having from 1 to 6carbon atoms; alkoxy groups having from 1 to 6 carbon atoms; hydroxygroups; halogen atoms; amino groups; alkylamino groups having from 1 to6 carbon atoms; dialkylamino groups in which each alkyl part has from 1to 6 carbon atoms; aliphatic acylamino groups having from 1 to 6 carbonatoms; cyano groups; nitro groups; and carboxy groups.

Compounds of formula V and methods of preparing compounds of formula Vare described in European Patent Application Publication Number 0567271A2, published Oct. 27, 1993. Said compounds are disclosed therein asbeing useful in inhibiting steroid 5α-reductase.

As used herein, unless otherwise specified, C_(1-n) alkyl and C_(1-n)alk means a straight or branched hydrocarbon chain having 1 to n carbonsand alk means a straight or branched hydrocarbon chain having 1 to 12carbons.

Preferably the substituted 3,5-diene steroidal compound for use in thepresently invented stabilized tablet formations and presently inventedmethods is N-t-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylicacid. N-t-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid canbe prepared as described in U.S. Pat. No. 5,017,568. This compound isdisclosed therein as being useful in inhibiting steroid 5α reductase.

Although stable when blended or granulated with one or more commonlyused pharmaceutical excipients such as, for example, lactose, tribasiccalcium phosphate, silicon dioxide, corn starch, sodium starchglycolate, hydroxypropyl cellulose, hydroxypropyl methylcellulose,gelatin, magnesium stearate, microcrystalline cellulose, mannitol, andsorbitol, substituted 3,5-diene steroidal compounds were unexpectedlyfound to undergo a significant increase in the rate of formation ofdegradation products when compressed into tablets with suchpharmaceutical excipients. This increase in degradation products occurswhether the substituted 3,5-diene steroidal compound and said excipientsare formulated in direct compression tablets or in wet granulationtablets.

As used herein, unless otherwise indicated, the term "tablet" andderivatives thereof, means a direct compression tablet or a wetgranulation tablet.

The reduction of degradation products of steroidal compounds inpharmaceutical formulations is of particular importance because minorchanges in the structure of steroids are known to produce profoundchanges in its biological activity. Moreover, steroidal compounds areknown to be extremely potent, often requiring only very low doses of thecompound to exhibit pharmaceutical activity.

It has now been found that the addition of a fatty acid, preferablystearic acid or palmitic acid; an antioxidant, preferably butylatedhydroxyanisol (BHA) or butylated hydroxytoluene (BHT), most preferablyBHT; or a combination of a fatty acid and an antioxidant, to a blend ofpharmaceutical excipients containing a substituted 3,5-diene steroidalcompound dramatically decreases the percentage of degradation productsof the active in subsequently compressed tablets. Said tablets areprepared by compression under normal operating conditions using astandard tablet press.

The stability ofN-t-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid (compoundA) in various tablet formulations was determined by HPLC analysis.Degradation products were analyzed by LC/MS and unexpectedly found to bethe result of oxidative additions (the 7 keto oxidation product andothers) which only occurred when blends or granulations of Compound Awere compressed into tablets. In order to reduce the percentage ofdegradation products to desired levels, preferably an increase of nomore than 0.2 percent from baseline at day 0 after two weeks in theAccelerated Stability Screening Method (described herein), numeroustablet formulations were prepared and analyzed as indicated below.

In order to facilitate research efforts an Accelerated StabilityScreening Method was developed. It was found that storing tablets at 85°C. for a short time (preferably two weeks) is suitable for predictinglong term stability at room temperature. This method was employed uponnoting that the degradation profiles generated at room temperature ascompared to 85° C. were similar and that the profiles generated fortablets prepared by either direct compression (dry granulation process)or fluid bed granulation (wet granulation process) are the same.

DIRECT COMPRESSION TABLETS

Experiments 1 and 2 were performed (utilizing Compound A) in order todetermine the most advantageous direct compression tablet formulationsof substituted 3,5-diene steroidal compounds.

EXPERIMENT 1

In Experiment 1 Compound A, microcrystalline cellulose, lactose, cornstarch and sodium starch glycolate shown in Table I below, were mixed inthe proportions shown. The mixture was split in half (into Batch 1 andBatch 2). Batch 1 was mixed with 1 percent magnesium stearate andcompressed into appropriately sized tablets preferably 300 mg to 350 mgtablets each containing from about 80 mg to 85 mg of active compound (nostearic acid group). Batch 2 was first mixed and granulated with 2percent stearic acid, then mixed and granulated with 1 percent magnesiumstearate and compressed into appropriately sized tablets preferably 300mg to 350 mg tablets each containing from about 80 mg to 85 mg of activecompound (stearic acid group). The tablets thus prepared were placed instability chamber at 85° and the results of the stability test wererecorded in Table 2 below.

                  TABLE 1    ______________________________________                         % w/w    ______________________________________    Batch 1     Compound A     10                Microcrystalline                               40                Cellulose                Lactose        32                Corn Starch    10                Sodium Starch Glycolate                               7                Mg Stearate    1    Batch 2     Compound A     10                Microcrystalline                               40                Cellulose                Lactose        32                Corn Starch    10                Sodium Starch Glycolate                               7                Stearic Acid   +2                Mg Stearate    1    ______________________________________

                  TABLE 2    ______________________________________            % Degradation                      % Degradation                                 % Degradation            Day 0     Day 4      Day 11    ______________________________________    Batch 1   0           0.05       0.17    (No Stearic Acid)    Batch 2   0           0.01       0.01    (Stearic Acid)    ______________________________________

EXPERIMENT 2

In Experiment 2 one gram of Compound A was mixed and granulated with tengrams of lactose. The mixture was split into three equal parts (Batch 3Batch 4 and Batch 5). Batch 3 was compressed into tablets of about 300mg to 350 mg, about 30 mg to 35 mg of active compound (Control group: noadditives). Batch 4 was mixed with two percent pure stearic acid andcompressed into tablets of about 300 mg to 350 mg, about 30 mg to 35 mgof active compound. Batch 5 was mixed with two percent pure palmiticacid and compressed into tablets of about 300 mg to 350 mg, about 30 mgto 35 mg of active compound. The tablets thus prepared were placed instability chamber at 85° C. and the results of the stability test wererecorded in Table 3 below.

                  TABLE 3    ______________________________________             % Degradation                      % Degradation                                  % Degradation             Day 0    Day 6       Day 11    ______________________________________    Batch 3    0          0.47        0.54    (Control)    Batch 4    0          0.03        0.04    (Pure Stearic Acid)    Batch 5    0          0.08        0.11    (Pure Palmitic Acid)    ______________________________________

Wet Granulation Process

Experiments 3 to 6 were performed (utilizing Compound A) in order todetermine the most advantageous wet granulation tablet formulations ofsubstituted 3,5-diene compounds. To perform the wet granulationexperiments a `Standard Granulation` containing Compound A was utilized.To prepare the Standard Granulation Compound A (generally about 37% ofthis mixture) and lactose (generally about 57% of this mixture) aremixed and granulated with about a 9% solution of hydroxypropylmethylcellulose (generally about 6% of this mixture). The wet granules arescreened and dried to form the Standard Granulation.

EXPERIMENT 3

In Experiment 3 Standard Granulation, corn starch, sodium starchglycolate, microcrystalline cellulose, magnesium stearate and stearicacid (for Batch 6) or additional magnesium stearate (for Batch 7) shownin Table 4 below, were blended in the proportions shown and compressedinto tablets of about 300 mg to 350 mg, about 80 mg to 85 mg of activecompound. The tablets thus prepared were placed in stability chamber at85° C. and the results of the stability test were recorded in Table 5below.

                  TABLE 4    ______________________________________    Batch 6    Standard Granulation    715 g    Stearic Acid            23 g    Corn Starch             49.5 g    Sodium Starch Glycolate 50 g    Microcrystalline Cellulose                            150 g    Magnesium Stearate      12.5 g    Batch 7    Standard Granulation    715 g    Magnesium Stearate      23 g    Corn Starch             49.5 g    Sodium Starch Glycolate 50 g    Microcrystalline Cellulose                            150 g    Magnesium Stearate      12.5 g    ______________________________________

                  TABLE 5    ______________________________________               % Degradation                        % Degradation               Day 0    Day 11    ______________________________________    Batch 6      0          0.13    Batch 7      0          0.31    ______________________________________

EXPERIMENT 4

In Experiment 4 Standard Granulation and BHT (for Batch 8) shown inTable 6 below, or stearic acid and BHT (for Batch 9) shown in Table 7below, were mixed and granulated in the proportions shown and compressedinto tablets of about 350 mg total tablet weight. The tablets thusprepared were placed in stability chamber at 85° C. and the results ofthe stability test were recorded in Tables 6 and 7 below.

                  TABLE 6    ______________________________________    Batch 8                 % Degradation                            % Degradation    % w/w BHT    Day 0      Day 14    ______________________________________    0            0          0.57    0.1          0          0.22    0.5          0          0.45    1.0          0          0.17    2.0          0          0.10    ______________________________________

                  TABLE 7    ______________________________________    Batch 9                          % Degradation                                      % Degradation    % w/w Stearic Acid                % w/w BHT Day 0       Day 14    ______________________________________    0.2         0.1       0           0.34    1.0         0.5       0           0.04    2.0         1.0       0           0.02    4.0         2.0       0           0.03    ______________________________________

EXPERIMENT 5

In Experiment 5 Standard Granulation (at about 72% w/w),microcrystalline cellulose (from 14% to 17% w/w depending on BHT andstearic acid content from Table 8) corn starch (at about 5% w/w), sodiumstarch glycolate (at about 5% w/w) and stearic acid and BHT (for Batch10) shown in Table 8 below, were mixed and granulated in the proportionsshown and compressed into 300 mg tablets (about 80 mg of Compound A).The tablets thus prepared were placed in stability chamber at 85° C. andthe results of the stability test were recorded in Table 8 below.

                  TABLE 8    ______________________________________    Batch 10                         % Degradation                                     % Degradation    % w/w Stearic Acid               % w/w BHT Day 0       Day 15    ______________________________________    0          0         0           0.75    0          0         0           0.59    0.5        0.25      0           0.1    1.0        0.52      0           0    1.6        0.79      0           0.03    2.0        1.05      0           0.01    2.0        1.05      0           0.03    ______________________________________

EXPERIMENT 6

In Experiment 6 Standard Granulation (at about 72% w/w),microcrystalline cellulose (from 16% to 17% w/w depending on BHT contentfrom Table 9), corn starch (at about 5% w/w), sodium starch glycolate(at about 5%) magnesium stearate (at about 1%), stearic acid (at about2%) and BHT (for Batch 11) shown in Table 9 below, were mixed andgranulated in the proportions shown and compressed into 300 mg tablets(about 80 mg of Compound A). The tablets thus prepared were placed instability chamber at 85° C. and the results of the stability test wererecorded in Table 9 below.

                  TABLE 9    ______________________________________    Batch 11             % Degradation                         % Degradation                                     % Degradation    % w/w BHT             Day 0       Day 7       Day 16    ______________________________________    0        0           0.12        0.19    0.1      0           0           0    0.25     0           0           0    0.5      0           0           0    1.0      0           0.01        0.03    ______________________________________

The data from the above experiments demonstrates the ability of thepresently discovered invention to stabilize direct compression tabletsand wet granulation tablets containing substituted 3,5-diene steroidalcompounds.

Fatty acids, particularly stearic acid, are known pharmaceuticalexcipients which are utilized in the art, primarily as tabletlubricants. Stearic acid, as a tablet lubricant, is consideredinterchangeable with other known tablet lubricants, particularlymagnesium stearate. As discovered herein, fatty acids are disclosed asexhibiting the previously unknown ability to stabilize tabletformulations of substituted 3,5-diene steroidal compounds when otherknown tablet lubricants, particularly magnesium stearate, and otherknown pharmaceutical excipients do not exhibit such activity. As such,the present invention also relates to the use of fatty acids, preferablystearic acid or palmitic acid, most preferably stearic acid, asstabilizing agents in tablet formulations, particularly tabletformulations of substituted 3,5-diene steroidal compounds.

Preferably the fatty acid will be present in the finished tablet, asprepared herein, in an amount from about 0.5% to about 10% by weight.

Most preferably the fatty acid will be present in the finished tablet,as prepared herein, in an amount from about 1% to about 3% by weight,most preferably about 2%.

By the term "stabilized", and derivatives thereof, as used herein ismeant that the subject substituted 3,5-diene steroidal compound whencompressed into a tablet, under normal operating conditions using astandard tablet press, with a blend of pharmaceutical excipients and afatty acid, an antioxidant or a combination of a fatty acid and anantioxidant will experience the formation of less degradation products,preferably less than one half of the degradation products, experiencedby said substituted 3,5-diene steroidal compound when compressed into atablet with the same blend of pharmaceutical excipients without suchfatty acid, such antioxidant or such combination of a fatty acid and anantioxidant. Assessing the ability of a fatty acid, an antioxidant or acombination of a fatty acid and an antioxidant to stabilize a particularsubstituted 3,5-diene steroidal compound is accomplished by comparingthe stability of tablets containing a blend of pharmaceuticalexcipients, the subject substituted 3,5-diene steroidal compound andsuch fatty acid, such antioxidant or such combination of a fatty acidand an antioxidant to tablets wherein the only difference is that saidfatty acid, said antioxidant or said combination of a fatty acid and anantioxidant is left out (as in Experiment 1) or substituted for byanother pharmaceutical excipient, such as magnesium stearate (as inExperiment 3).

This invention provides for a method of stabilizing tablet formulationsof substituted 3,5-diene steroidal compounds which comprises:

(a) admixing a fatty acid, an antioxidant or a combination of a fattyacid and an antioxidant with a pharmaceutical excipient blend and asubstituted 3,5-diene steroidal compound;

(b) compressing the resulting mixture into tablets.

This invention also provides for a pharmaceutical formulation in tabletform comprising: a pharmaceutical excipient blend, a substituted3,5-diene steroidal compound and a fatty acid, an antioxidant or acombination of a fatty acid and an antioxidant, preferably stearic acidfor a direct compression tablet; preferably a combination of stearicacid and BHT for a wet granulation tablet.

By the term "pharmaceutical excipient blend" and derivatives thereof, asused herein is meant a mixture, a granulation or an admix of a mixtureand a gramulation of a plurality of commonly used pharmaceuticalexcipients, such as lactose, tribasic calcium phosphate, silicondioxide, corn starch, sodium starch glycolate, hydroxypropyl cellulose,hydroxypropyl methylcellulose, gelatin, magnesium stearate,microcrystalline cellulose, mannitol or sorbitol, excluding fatty acidsand antioxidants. Preferably when a pharmaceutical excipient blend, asdefined herein, is utilized in a granulation, said granulation will alsocontain a substituted 3,5-diene steroidal compound.

In the presently invented methods and in the presently invented tabletformulations preferred antioxidants for use herein are butylatedhydroxyanisol (BHA) and butylated hydroxytoluene (BHT), most preferablyBHT, preferably in an amount of from about 0.05% to about 2% by weight,more preferably from about 0.1% to about 1% by weight, most preferablyabout 0.25% by weight.

Contemplated equivalents of substituted 3,5-diene steroidal compoundsfor use herein are compounds of the formula: ##STR11## wherein W is anelectron-withdrawing group; and the C₁ and C₂ positions and the C₈ toC₁₀ positions are optionally substituted with pharmaceuticallyacceptable substituents, degrees of unsaturation, a combination ofpharmaceutically acceptable substituents and degrees of unsaturation orform part of a larger multicyclic compound.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following Examples are, therefore, to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention.

All of the excipients utilized herein are standard pharmaceutical gradeexcipients available from numerous manufactures well known to those inthe art, except that pure stearic acid and pure palmitic acid (fromExperiment 2), are not considered pharmaceutical grade and were obtainedfrom the Aldrich Chemical Company Milwaukee, Wis. Standard gradepharmaceutical excipients, from any reputable source, are consideredsuitable for use herein.

EXAMPLE 1

dry granulation process

The lactose, microcrystalline cellulose, sodium starch glycolate,stearic acid, magnesium stearate andN-t-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid shown inTable 10 below, are blended in the proportions shown. The dry granulesare screened and compressed into tablets. Said tablets are optionallycoated with, for example, a film coat. The procedure of Example I willproduce approximately 750,000 tablets of approximately 133 mg eachcontaining about 20 mg of the active ingredient.

                  TABLE 10    ______________________________________    Ingredients               Amounts    ______________________________________    N-t-butyl-androst-3,5-diene-17β-carboxamide-3-                              15,000 g    carboxylic acid    Microcrystalline Cellulose                              15,000 g    Lactose                   62,500 g    Sodium Starch Glycolate   5,000 g    Stearic Acid              2,000 g    Magnesium Stearate        500 g    ______________________________________

EXAMPLE 2

wet granulation process

The lactose; sodium starch glycolate; microcrystalline cellulose; andN-t-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid shown inTable 11 below, are mixed and granulated in the proportions shown with a9% solution of the hydroxypropylmethyl cellulose. The wet granules arescreened, dried, mixed with the stearic acid; magnesium stearate andbutylated hydroxytoluene, screened and compressed into tablets. Saidtablets are optionally coated with for example a film coat. Theprocedure of Example 2 will produce approximately 374,000 tablets ofapproximately 267 mg each containing about 80 mg of the activeingredient.

                  TABLE 11    ______________________________________    Ingredients               Amounts    ______________________________________    N-t-butyl-androst-3,5-diene-17β-carboxamide-3-                              30,000 g    carboxylic acid    Lactose                   25,000 g    Sodium Starch Glycolate   5,000 g    Microcrystalline Cellulose                              32,000 g    Hydroxypropylmethyl Cellulose                              4,000 g    Stearic Acid              3,000 g    Magnesium Stearate        500 g    Butylated hydroxytoluene  500 g    ______________________________________

While the preferred embodiments of the invention are illustrated by theabove, it is to be understood that the invention is not limited to theprecise instructions herein disclosed and that the right to allmodifications coming within the scope of the following claims isreserved.

What is claimed is:
 1. A pharmaceutical formulation in tablet form consisting of: a) N-t-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid, b) pharmaceutical excipients, and c) from about 0.5% to about 10% of fatty acid stabilizing lubricant. 